Identification and validation of colorectal neoplasia-specific methylation biomarkers based on CTCF-binding sites
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Jiang Liu1,*, Zhaoli Ding2,3,*, Guimei Li2,3,*, Li Tang1, Yu Xu4, Huayou Luo4, Jinhua Yi4, Youwang Lu4, Rui Mao5, Qiong Nan6, Li Ren7, Tong Zhang4 and Kunhua Wang4
1Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
2Public Technical Service Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650032, Yunnan, China
3Kunming Biological Diversity Regional Center of Large Apparatus and Equipments, Chinese Academy of Sciences, Kunming 650032, Yunnan, China
4Department of Gastrointestinal Surgery, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan, China
5School of Stomatology, Kunming Medical University, Kunming 650500, Yunnan, China
6Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan, China
7The First People’s Hospital of Yunnan Province, Kunming 650031, Yunnan, China
*These authors have contributed equally to this work
Kunhua Wang, email: kunhuawangProf@163.com
Keywords: colorectal cancer; early-detection; CTCF-binding site; DNA methylation; biomarker
Received: October 12, 2017 Accepted: November 22, 2017 Published: December 11, 2017
To date, the sensitivity of currently available biomarkers based on the methylation of gene promoters is suboptimal for detecting adenomas and early-stage colorectal cancer (CRC). We aimed to develop biomarkers with methylated DNA binding sites of the multifunctional transcriptional factor CTCF for early detection of CRC. Using combined analyses of genome-wide occupation and the methylation profile of CTCF-binding sites, we identified candidate CTCF-binding sites. Then, we applied methylation-sensitive high-resolution melting (MS-HRM) and mass spectrometry analysis to screen and validate these candidate sites in diverse sample sets. We identified a set of colorectal neoplasia-specific biomarkers with robust performance. The top five biomarkers were selected and recommended for early detection of colorectal neoplasia. All of the five novel biomarkers exhibited a more robust discriminatory performance than that by BMP3 and NDRG4, two currently acknowledged robust methylation biomarkers. When the five new biomarkers were considered as a marker panel and tumor-positive was defined as having two or more (of the five) positive biomarkers, the marker panel could achieve a sensitivity of 91.67% for adenomas, 97.44% for Stage I CRC, 94.06% for Stage II CRC, 93.62% for Stage III CRC, and 93.54% for total colorectal tumors with a specificity of 94.05%. To our knowledge, this is the first study for colorectal neoplasia-specific methylation biomarkers based on CTCF-binding sites. Using a similar strategy, CTCF-binding sites could be potentially developed into biomarkers for other tumors. In summary, this study opens a new area in developing biomarkers for tumor prevention and treatment.
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